PMSA 可防止小鼠的破骨细胞生成和雌激素依赖性骨质流失,Bone

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PMSA 可防止小鼠的破骨细胞生成和雌激素依赖性骨质流失
Bone ( IF 3.5 ) Pub Date : 2021-01-01 , DOI: 10.1016/j.bone.2020.115707
Eunjin Cho ₁ , Zhihao Chen ₂ , Mina Ding ₂ , Jihyoun Seong ₁ , Sunwoo Lee ₃ , Sang Hyun Min ₄ , Dong Kyu Choi ₄ , Tae-Hoon Lee ₅

Affiliation

由成熟破骨细胞介导的过度骨吸收可导致骨质疏松症，导致脆性骨折。因此，抗骨质疏松药物的有效治疗策略是降低破骨细胞活性。在这项研究中，研究了一种新型化合物 N-苯基-甲基磺酰胺-乙酰胺 (PMSA) 的破骨细胞抑制活性。PMSA 治疗抑制了核因子 kappa B 配体 (RNAKL) 的受体激活剂诱导的骨髓来源巨噬细胞 (BMM) 中的破骨细胞分化。我们研究了两种 PMSA，N-2-(3-乙酰苯基)-N-2-(甲基磺酰基)-N-1-[2-(苯硫基)苯基]甘氨酰胺 (PMSA-3-Ac) 和 N-2-( 5-氯-2-甲氧基苯基)-N-2-(甲基磺酰基)-N-1-[2-(苯硫基)苯基]甘氨酰胺(PMSA-5-Cl)，以确定它们对破骨细胞分化的影响。PMSAs 在早期抑制信号通路。PMSA-3-Ac 抑制肿瘤坏死因子受体相关因子 6 (TRAF6) 表达，而 PMSA-5-Cl 抑制丝裂原活化蛋白激酶 (MAPK) 信号通路。然而，这两种 PMSA 通过阻断核定位来抑制主转录因子，即活化 T 细胞胞质 1 (NFATc1) 的核因子。在卵巢切除 (OVX) 小鼠模型中对 PMSA 进行了体内研究，PMSA-5-Cl 可防止 OVX 小鼠的骨质流失。因此，我们的结果表明 PMSA，特别是 PMSA-5-Cl，可以作为绝经后骨质疏松症的潜在治疗剂。而 PMSA-5-Cl 抑制丝裂原活化蛋白激酶 (MAPK) 信号通路。然而，这两种 PMSA 通过阻断核定位来抑制主转录因子，即活化 T 细胞胞质 1 (NFATc1) 的核因子。在卵巢切除 (OVX) 小鼠模型中对 PMSA 进行了体内研究，PMSA-5-Cl 可防止 OVX 小鼠的骨质流失。因此，我们的结果表明 PMSA，特别是 PMSA-5-Cl，可以作为绝经后骨质疏松症的潜在治疗剂。而 PMSA-5-Cl 抑制丝裂原活化蛋白激酶 (MAPK) 信号通路。然而，这两种 PMSA 通过阻断核定位来抑制主转录因子，即活化 T 细胞胞质 1 (NFATc1) 的核因子。在卵巢切除 (OVX) 小鼠模型中对 PMSA 进行了体内研究，PMSA-5-Cl 可防止 OVX 小鼠的骨质流失。因此，我们的结果表明 PMSA，特别是 PMSA-5-Cl，可以作为绝经后骨质疏松症的潜在治疗剂。

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PMSA Prevents Osteoclastogenesis and Estrogen-Dependent Bone Loss in Mice

Excessive bone resorption mediated by mature osteoclasts can cause osteoporosis, leading to fragility fractures. Therefore, an effective therapeutic strategy for anti-osteoporosis drugs is the reduction of osteoclast activity. In this study, the osteoclast inhibitory activity of a novel compound, N-phenyl-methylsulfonamido-acetamide (PMSA), was examined. PMSA treatment inhibited receptor activator of nuclear factor kappa B ligand (RNAKL)-induced osteoclast differentiation in bone marrow-derived macrophage cells (BMMs). We investigated two PMSAs, N-2-(3-acetylphenyl)-N-2-(methylsulfonyl)-N-1-[2-(phenylthio)phenyl] glycinamide (PMSA-3-Ac), and N-2-(5-chloro-2-methoxyphenyl)-N-2-(methylsulfonyl)-N-1-[2-(phenylthio)phenyl]glycinamide (PMSA-5-Cl), to determine their effects on osteoclast differentiation. PMSAs inhibited the signaling pathways at the early stage. PMSA-3-Ac inhibited tumor necrosis factor receptor-associated factor 6 (TRAF6) expression, whereas PMSA-5-Cl suppressed the mitogen-activated protein kinase (MAPK) signaling pathways. However, both PMSAs inhibited the master transcription factor, nuclear factor of activated T cell cytoplasmic-1 (NFATc1), by blocking nuclear localization. An in vivo study of PMSAs was performed in an ovariectomized (OVX) mouse model, and PMSA-5-Cl prevented bone loss in OVX mice. Therefore, our results suggested that PMSAs, specifically PMSA-5-Cl, may serve as a potential therapeutic agent for postmenopausal osteoporosis.

更新日期：2021-01-01

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